We acknowledge transient myocardial ischemia as an obligate companion of major trauma. Post-traumatic cardiac dysfunction compromises early host repair and exacerbates late multiple organ failure. Post-ischemic reperfusion is associated with an oxidant burst which in hepatocytes, Kupffer cells and blood monocytes promotes TNF production. We propose that myocardium (both cardiomyocytes and resident macrophage) can generate TNF. We postulate that: post-traumatic myocardial ischemia/reperfusion (I/R) induces endogenous cardiac TNF production with resultant functional depression. Although multiple inflammatory stimuli and several cell signalling routes can induce macrophage TNF release, we note that I/R induced oxidants activate both P38 MAP kinase (P38 MAPK) and nuclear factor kappaB (NRkappaB). We further hypothesize that: Post-traumatic I/R generates oxidants which activate both P38 MAPK and NFkappaB in human myocardium. Strategies targeting post-injury P38 MAPK and NFkappaB should reduce endogenous myocardial TNF production and improve post-traumatic cardiac function. In concert with Projects III and VIII we plan to examine the post ischemia/injury signals that lead to endogenous myocardial TNF production. We then propose to determine post-ischemic myocardial TNF protein content, TNF bioactivity, TNF subcellular localization, P38 MAPK activation, NFkappaB subcellular localization and cardiac function following both pharmacologic and heat shock protein-72 liposomal transfer (in conjunction with Project V) strategies of inhibiting TNF production. We accept transient myocardial ischemia as an obligate sequela of major trauma. Post-traumatic cardiac dysfunction compromises early host organ repair and exacerbates late multiple organ failure. Post-ischemic reperfusion is associated with an oxidant burst which in hepatocytes, Kupffer cells and blood monocytes promotes TNF production by activating signals through P38 map kinase and nuclear factor kappaB. We hypothesize: Global hypothesis: Post-traumatic ischemia/reperfusion induces endogenous cardiac TNF production with resultant mechanical cardiac depression. We also postulate that post-injury I/R generates oxidants which activate both P38 MAPK and NFkappaB in human myocardium.